US4321254A - Antiallergic imidodisulfamides - Google Patents

Antiallergic imidodisulfamides Download PDF

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Publication number
US4321254A
US4321254A US06/191,644 US19164480A US4321254A US 4321254 A US4321254 A US 4321254A US 19164480 A US19164480 A US 19164480A US 4321254 A US4321254 A US 4321254A
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Prior art keywords
methyl
chloro
hydrogen
bromo
trifluoromethyl
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US06/191,644
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English (en)
Inventor
Fadia E. Ali
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SmithKline Beecham Corp
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SmithKline Corp
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Assigned to SMITHKLINE CORPORATION reassignment SMITHKLINE CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ALI FADIA E.
Priority to US06/191,644 priority Critical patent/US4321254A/en
Priority to GR66121A priority patent/GR75053B/el
Priority to DK420781A priority patent/DK420781A/da
Priority to JP56151345A priority patent/JPS5785370A/ja
Priority to IE2228/81A priority patent/IE51596B1/en
Priority to AT81304449T priority patent/ATE7024T1/de
Priority to DE8181304449T priority patent/DE3163096D1/de
Priority to EP81304449A priority patent/EP0049135B1/en
Publication of US4321254A publication Critical patent/US4321254A/en
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Assigned to SMITHKLINE BECKMAN CORPORATION reassignment SMITHKLINE BECKMAN CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). EFFECTIVE DATE: 03/04/82 Assignors: SMITHKLINE CORPORATION
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom

Definitions

  • This invention relates to novel imidodisulfamides which are useful as end-organ antagonists of slow reacting substance of anaphylaxis, pharmaceutical compositions and methods of inhibiting the symptoms of an allergic response.
  • the substance, SRS-A has been suggested to be an important mediator of anaphylaxis in human asthma. By antagonizing the effects of this or other pharmacologically active mediators at the end-organ, bronchial smooth muscle, the compounds of this invention are valuable in the treatment of allergic diseases such as asthma.
  • the imidodisulfamide compounds of this invention are represented by the following general structural formula (I): ##STR1## wherein X is hydrogen, bromo or chloro; and Y is a phenylsulfonamido radical of the formula: ##STR2## wherein R is hydrogen or methyl; R 1 is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2 is hydrogen, chloro or methyl provided that when R 2 is chloro, R 1 is chloro, methyl or trifluoromethyl, and when R 2 is methyl, R 1 is methyl; or an alkali metal salt of said compounds.
  • R is hydrogen or methyl
  • R 1 is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy
  • R 2 is hydrogen, chloro or methyl provided that when R 2 is chloro, R 1 is chloro, methyl or trifluoromethyl, and when R 2 is methyl, R 1 is methyl
  • non-nucleophilic organic bases examples include tertiary alkylamines, such as triethylamine, tertiary alkylaryl amines, such as N,N-dimethylaniline and aromatic amines, such as pyridine.
  • the reaction is carried out in an inert polar organic solvent.
  • a particular solvent is not critical provided that the solvent is substantially inert to the reagents and product.
  • Illustrative of such a solvent is acetonitrile.
  • the reaction is usually carried out at moderate to low temperatures.
  • the reagents are usually mixed at temperatures of 0° C. or less and the reaction is allowed to warm gradually to ambient temperature.
  • reaction time is dependent on inter alia the particular starting materials, solvent and reaction temperature. Generally, the reaction will be allowed to proceed for at least 12 hours.
  • reaction product can be isolated by standard methods for example addition of dilute mineral acid e.g. hydrochloric acid, to the reaction mixture affords the compounds of formula (I) as the "free acid".
  • dilute mineral acid e.g. hydrochloric acid
  • Alkali metal salts of the compounds of the formula (I), for example, the sodium or potassium salts are obtainably by treatment of the compounds with the appropriate metal alkoxide, for example methoxide, in an alkanol solvent such as methanol; by treatment of the compounds with an alkali metal hydride, such as sodium hydride or potassium hydride, in a polar non-protic solvent, such as tetrahydrofuran, or dimethoxyethane; or by treatment of the compounds with a cationic exchange resin, such as a sulfonic acid resin in the sodium form.
  • the appropriate metal alkoxide for example methoxide
  • an alkanol solvent such as methanol
  • an alkali metal hydride such as sodium hydride or potassium hydride
  • a polar non-protic solvent such as tetrahydrofuran, or dimethoxyethane
  • a cationic exchange resin such as a sulfonic acid resin in the sodium form.
  • Illustrative of the instant invention wherein the tetrahydroisoquinoline moiety is substituted in the 7-position with a phenylsulfonamido group are compounds of the formula (II).
  • X 1 is hydrogen, methyl, bromo or chloro
  • R represents hydrogen or methyl
  • R 1 represents hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy
  • R 2 represents hydrogen, chloro or methyl provided that when R 2 is chloro, R 1 is chloro, methyl or trifluoromethyl and when R 2 is methyl, R 1 is methyl or an alkali metal salt of the compounds of the formula (II).
  • Particular compounds of the instant invention are the compounds of formula (II) wherein X 1 is hydrogen.
  • R and R 2 both represent hydrogen and R 1 represents hydrogen; 2-, 3- or 4-bromo; 2-, 3- or 4-chloro; 3-nitro; 3- or 4-trifluoromethyl; or 4-methoxy;
  • R represents hydrogen; R 2 represents 4-chloro; and R 1 represents 3-trifluoromethyl;
  • R represents hydrogen; R 2 represents 3-methyl; and R 1 represents 4-methyl;
  • R represents methyl; R 2 represents hydrogen; and R 1 represents 2-, 3- or 4-chloro.
  • compounds included in the instant invention are of the formula (II) wherein X 1 , R and R 2 represent hydrogen, and R 1 represents 4-chloro or 4-bromo and wherein X 1 and R represent hydrogen, R 2 represents 3-methyl and R 1 represents 4-methyl.
  • the starting substituted tetrahydroisoquinoline (A) may be prepared from amino tetrahydroisoquinoline (B) via the following synthetic pathway: ##STR6##
  • the compound (B) is reacted with the appropriately substituted benzenesulfonylchloride followed by treatment with dilute mineral acid to give the appropriately substituted tetrahydroisoquinoline (A).
  • Bis(chlorosulfonyl)imide is prepared from chlorosulfonic acid and chlorosulfonylisocyanate.
  • the amino tetrahydroisoquinoline starting materials used as above are obtained by standard reactions well known in the art.
  • the starting amino tetrahydroisoquinolines may be prepared from the corresponding hydroxy-2-acetyl-tetrahydroisoquinoline via a standard Bucherer reaction followed by hydrolysis of the acetyl moiety.
  • the starting amino tetrahydroisoquinolines may be prepared from the corresponding hydroxyisoquinoline via a standard Bucherer reaction followed by diborane hydrogenation of the amino isoquinoline intermediate.
  • the starting amino tetrahydroisoquinoline may also be prepared by the stannous chloride reduction of the corresponding nitrotetrahydroisoquinoline.
  • the benzenesulfonylchloride compounds are known.
  • Illustrative of the instant invention wherein the tetrahydroisoquinoline moiety is substituted in the 6-position with a phenylsulfonamido group are compounds of the formula (III): ##STR7## wherein X 2 is methyl, bromo, or chloro; R is hydrogen or methyl; R 1 is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2 is hydrogen, chloro or methyl provided that when R 2 is chloro, R 1 is chloro, methyl or trifluoromethyl and when R 2 is methyl, R 1 is methyl or an alkyl metal salt of said compounds.
  • the amino tetrahydroisoquinoline (C) is converted into compounds of the formula (III) by reacting compound (C) with the appropriately substituted benzenesulfonylchloride followed by hydrolysis to give compound (D) which is then coupled with bis(chlorosulfonyl)imide.
  • amino tetrahydroisoquinoline starting materials used as above are obtained by standard reactions well-known in the art.
  • the benzenesulfonylchloride compounds are known.
  • Illustrative of the instant invention wherein the tetrahydroisoquinoline moiety is substituted in the 8-position with a phenylsulfonamido group are compounds of the formula (IV) ##STR9## wherein X 3 is hydrogen, methyl, bromo or chloro; R is hydrogen or methyl; R 1 is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2 is hydrogen, chloro or methyl provided that when R 2 is chloro, R 1 is chloro, methyl or trifluoromethyl and when R 2 is methyl, R 1 is methyl or an alkali metal salt thereof.
  • a particular compound of the instant invention of the formula (IV) is the compound wherein X 3 is 7-chloro; R and R 3 are each hydrogen; and R 1 is 3-chloro.
  • amino tetrahydroisoquinoline starting materials used as above are obtained by standard reactions well-known in the art.
  • the benzenesulfonylchloride compounds are known.
  • Illustrative of the instant invention wherein the tetrahydroisoquinoline moiety is substituted in the 5-position with a phenylsulfonamide group are compounds of the formula (V) ##STR11## wherein X 4 is methyl, bromo or chloro; R is hydrogen or methyl; R 1 is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2 is hydrogen, chloro or methyl provided that when R 2 is chloro, R 1 is chloro, methyl or trifluoromethyl and when R 2 is methyl, R 1 is methyl or an alkali metal salt of said compounds.
  • a particular compound of the instant invention is a compound of the formula (V) wherein X 4 is 8-chloro; R and R 2 are each hydrogen; and R 1 is 3-chloro.
  • amino tetrahydroisoquinoline starting materials used as above are obtained by standard reactions well-known in the art.
  • the benzenesulfonylchloride compounds are known.
  • the SRS-A antagonist activity of the compounds of this invention is measured by the ability of the active medicament to inhibit SRS-A induced contraction of guinea pig ileum.
  • sections of ileum are resected from guinea pigs and placed in 5 ml. tissue baths containing a modified Tyrode's solution. One end of the tissue is fixed to a glass tissue holder, the other is connected to a force-displacement transducer and the tissue is placed under a tension of 500 mg. Isometric tissue contractions are recorded on a six channel polygraph. Baths are constantly aerated with 95% O 2 -5% CO 2 .
  • a concentration of the appropriate agonist which provides a contraction height of 60-80% of the maximum obtainable to that agonist (as determined) from full sequential concentration--response curves in separate experiments) is added to the tissue bath and the response recorded. The procedure is repeated until reproducible responses are obtained. For most agonist, two applications in rapid succession, followed 15 minutes later by a third, is sufficient to establish reproducibility.
  • Experimental tissues are incubated with the selected concentration of the test compounds for 15 minutes. Experimental and control tissues are subjected to 5 bath changes during the incubation interval. Changes in bath fluid during the incubation period are helpful in insuring the reproducibility of tissue responses to the agonist.
  • the same concentration of the agonist is reapplied in the presence of the test compound and the response registered and compared with controls.
  • Percent inhibition produced by the test compound is calculated by substracting the mean percentage change in control tissue from the mean percentage change in tissues exposed to the test compound. Additional compounds are then evaluated as long as the tissue remains reproducibly responsive to the agonist. Six tissues obtained from 6 animals are used simultaneously-3 controls and 3 experimental.
  • the compounds of this invention tested at concentrations of from 5 ⁇ 10 -5 M to 1 ⁇ 10 -6 M produce marked antagonism of partially purified slow reacting substance of anaphylaxis obtained from guinea pig lung.
  • the agonist is employed at a concentration of 40 ⁇ g/ml.
  • the specificity of the antagonist activity of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, serotonin, histamine and the prostaglandins F 2 ⁇ and E 2 .
  • compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the formula (I) or an alkali metal salt thereof sufficient to produce the inhibition of the symptoms of asthma and other allergic diseases.
  • examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, gylcerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoro ethane and compressed carbon dioxide.
  • the instant compositions may include other ingredients such as, stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
  • compositions and the pharmaceutical carrier or diluent will of course depend upon the intended route of administration, i.e. parenterally or by inhalation.
  • the compositions will be in a form suitable for administration by inhalation.
  • the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer.
  • the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container.
  • the compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device.
  • the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in less, equal or greater amounts than the solid active ingredient.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension.
  • a compound of formula I is administered to an animal or human subject in a composition comprising an amount sufficient to produce an inhibition of the symptoms of an allergic response.
  • the dosage of the composition is such that from 0.5 mg. to 500 mg. of active ingredient are administered at each administration.
  • equal doses will be administered 1 to 4 times daily with the daily dosage regimen being selected from about 0.5 mg. to about 2000 mg.
  • the method of inhibiting the symptoms of an allergic response resulting from a mediator release which comprises administering to an animal or human subject a therapeutically effective amount for producing said inhibition of a compound of formula I, preferably in the form of a pharmaceutical composition.
  • the administration may be carried out in dosage units at suitable intervals or in single doses as needed.
  • the method of this invention will be practiced when relief of allergic symptoms is specifically required, however, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the allergic condition being treated, and so forth.
  • the reaction mixture was concentrated under reduced pressure at less than 35° C.
  • the residue was dissolved in methylene chloride and washed with dilute hydrochloric acid and then with water.
  • the methylene chloride solution was then dried over anhydrous sodium sulfate and concentrated to dryness at reduced pressure to afford the crude product.
  • the crude product was partitioned between ethyl acetate and dilute hydrochloric acid.
  • the ethyl acetate fraction was dried over anhydrous sodium sulfate and the product recrystallized from ethyl acetate-petroleum ether.
  • N,N'-bis[7-(4-chlorophenylsulfonamido)-1,2,3,4-tetrahydroisoquinoline]disulfonylimide was a solid with a melting point of 130°-192° C. (dec.).
  • alkali metal salts of the compounds of the present invention may be prepared.
  • an active ingredient such as N,N'-bis[7-(4-chlorophenylsulfonamido)-1,2,3,4-tetrahydroisoquinolyl]disulfonylimide, is dissolved in sterile water at a concentration of 0.5% and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
US06/191,644 1980-09-26 1980-09-26 Antiallergic imidodisulfamides Expired - Lifetime US4321254A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US06/191,644 US4321254A (en) 1980-09-26 1980-09-26 Antiallergic imidodisulfamides
GR66121A GR75053B (enrdf_load_stackoverflow) 1980-09-26 1981-09-23
DK420781A DK420781A (da) 1980-09-26 1981-09-23 Antiallergiske imidodisulfamider
JP56151345A JPS5785370A (en) 1980-09-26 1981-09-24 Antiallergic imidodisulfamides, manufacture and medicinal composition containing same
IE2228/81A IE51596B1 (en) 1980-09-26 1981-09-25 Antiallergic imidodisulfamides
AT81304449T ATE7024T1 (de) 1980-09-26 1981-09-25 Antiallergische imidodisulfamide.
DE8181304449T DE3163096D1 (de) 1980-09-26 1981-09-25 Antiallergic imidodisulfamides
EP81304449A EP0049135B1 (en) 1980-09-26 1981-09-25 Antiallergic imidodisulfamides

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US06/191,644 US4321254A (en) 1980-09-26 1980-09-26 Antiallergic imidodisulfamides

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US4321254A true US4321254A (en) 1982-03-23

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US06/191,644 Expired - Lifetime US4321254A (en) 1980-09-26 1980-09-26 Antiallergic imidodisulfamides

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US (1) US4321254A (enrdf_load_stackoverflow)
EP (1) EP0049135B1 (enrdf_load_stackoverflow)
JP (1) JPS5785370A (enrdf_load_stackoverflow)
AT (1) ATE7024T1 (enrdf_load_stackoverflow)
DE (1) DE3163096D1 (enrdf_load_stackoverflow)
DK (1) DK420781A (enrdf_load_stackoverflow)
GR (1) GR75053B (enrdf_load_stackoverflow)
IE (1) IE51596B1 (enrdf_load_stackoverflow)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350698A (en) * 1981-09-25 1982-09-21 Smithkline Corporation Antiallergic imidosulfamides
US4562182A (en) * 1980-12-23 1985-12-31 Beecham Group P.L.C. Compounds containing beta-lactams
US4571392A (en) * 1977-05-19 1986-02-18 Beecham Group Limited 6-Substituted derivatives of clavulanic acid
US4584291A (en) * 1980-12-09 1986-04-22 Beecham Group P.L.C. 9-deoxy-9-tetrazolyl-derivatives of clavulanic acid, their preparation and their use
US4652560A (en) * 1979-08-03 1987-03-24 Beecham Group P.L.C. A-deoxy-a-aza derivatives of clavulanic acid, a process for their preparation and their use
EP0300725A1 (en) * 1987-07-22 1989-01-25 Smith Kline & French Laboratories Limited Tetrahydroisoquinolin-2-yl derivatives as thromboxane A2 antagonists
US4812573A (en) * 1986-10-28 1989-03-14 Smithkline & French Laboratories, Ltd. Pharmaceutically active compounds
US6593341B2 (en) 2001-03-29 2003-07-15 Molecular Design International, Inc. β3-adrenoreceptor agonists, agonist compositions and methods of making and using the same
US6596734B1 (en) 2002-10-11 2003-07-22 Molecular Design International, Inc. Tetrahydroisoquinoline compounds for use as β3-adrenoreceptor agonists
US20040019079A1 (en) * 1997-09-30 2004-01-29 Feller Dennis R. Beta3-Adrenoreceptor agonists, agonist compositions and methods of using
US20070043026A1 (en) * 2002-05-10 2007-02-22 Cooper David G Dopamine receptor modulators as antipsychotic agents

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USRE24763E (en) 1960-01-12 Ch ch j
US3882148A (en) * 1971-07-29 1975-05-06 Fisons Ltd Chrome compounds having SRS{13 A properties
US4252818A (en) * 1979-08-02 1981-02-24 Merck & Co., Inc. Novel benzopyran derivatives

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US3549640A (en) * 1967-11-03 1970-12-22 Mallinckrodt Chemical Works N-alkylsulfinylalkyl- and sulfonylalkyl-1,2,3,4-tetrahydroisoquinolines
AT352135B (de) * 1975-07-30 1979-09-10 Thomae Gmbh Dr K Verfahren zur herstellung neuer homophthalimide und ihrer salze
DE2734222A1 (de) * 1977-07-29 1979-02-15 Thomae Gmbh Dr K Neue schwefelhaltige isochinolindione

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
USRE24763E (en) 1960-01-12 Ch ch j
US3882148A (en) * 1971-07-29 1975-05-06 Fisons Ltd Chrome compounds having SRS{13 A properties
US4252818A (en) * 1979-08-02 1981-02-24 Merck & Co., Inc. Novel benzopyran derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Appleton, et al., "J. Med. Chem.", vol. 20, No. 3, 1977, pp. 371-379. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571392A (en) * 1977-05-19 1986-02-18 Beecham Group Limited 6-Substituted derivatives of clavulanic acid
US4652560A (en) * 1979-08-03 1987-03-24 Beecham Group P.L.C. A-deoxy-a-aza derivatives of clavulanic acid, a process for their preparation and their use
US4584291A (en) * 1980-12-09 1986-04-22 Beecham Group P.L.C. 9-deoxy-9-tetrazolyl-derivatives of clavulanic acid, their preparation and their use
US4562182A (en) * 1980-12-23 1985-12-31 Beecham Group P.L.C. Compounds containing beta-lactams
US4350698A (en) * 1981-09-25 1982-09-21 Smithkline Corporation Antiallergic imidosulfamides
US4812573A (en) * 1986-10-28 1989-03-14 Smithkline & French Laboratories, Ltd. Pharmaceutically active compounds
EP0300725A1 (en) * 1987-07-22 1989-01-25 Smith Kline & French Laboratories Limited Tetrahydroisoquinolin-2-yl derivatives as thromboxane A2 antagonists
AU608339B2 (en) * 1987-07-22 1991-03-28 Smith Kline & French Laboratories Limited Sulphonamide-substituted isoquinolines
US20040019079A1 (en) * 1997-09-30 2004-01-29 Feller Dennis R. Beta3-Adrenoreceptor agonists, agonist compositions and methods of using
US6825213B2 (en) 1997-09-30 2004-11-30 Molecular Design International, Inc. β3-adrenoreceptor agonists, agonist compositions and methods of using
US20050096347A1 (en) * 1997-09-30 2005-05-05 Molecular Design International, Inc. Beta3-Adrenoreceptor agonists, agonist compositions and methods of using
US7119103B2 (en) 1997-09-30 2006-10-10 Molecular Design International, Inc. β3-Adrenoreceptor agonists, agonist compositions and methods of using
US6593341B2 (en) 2001-03-29 2003-07-15 Molecular Design International, Inc. β3-adrenoreceptor agonists, agonist compositions and methods of making and using the same
US20070043026A1 (en) * 2002-05-10 2007-02-22 Cooper David G Dopamine receptor modulators as antipsychotic agents
US6596734B1 (en) 2002-10-11 2003-07-22 Molecular Design International, Inc. Tetrahydroisoquinoline compounds for use as β3-adrenoreceptor agonists

Also Published As

Publication number Publication date
ATE7024T1 (de) 1984-04-15
IE51596B1 (en) 1987-01-21
DE3163096D1 (de) 1984-05-17
GR75053B (enrdf_load_stackoverflow) 1984-07-13
EP0049135B1 (en) 1984-04-11
IE812228L (en) 1982-03-26
JPS5785370A (en) 1982-05-28
EP0049135A1 (en) 1982-04-07
DK420781A (da) 1982-03-27

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